Clinical Trial Results:
Title: A Phase 3, Randomized, Double-Blind Trial of Two Formulations of Setmelanotide (Daily and Weekly) With a Crossover to Open Label Once Weekly Setmelanotide in Patients with Specific Gene Defects in the Melanocortin-4 Receptor Pathway Who Are Currently on a Stable Dose of the Once Daily Formulation. Trial design: This was a double-blind, double-dummy, randomised, crossover to open-label, multicentre study designed to compare the PK, safety, and efficacy of the QW (once weekly) and QD (once daily) subcutaneous (SC) formulations of setmelanotide, as well as the safety and efficacy after 6 months of QW setmelanotide in patients with BBS, biallelic PPL, or heterozygous PPL. In total, 19 patients, aged 8 to 37 years, who had taken QD setmelanotide in trial RM-493-022 (long-term extension [LTE] trial) for at least 6 months with acceptable safety and tolerability were treated. At screening, a daily hunger questionnaire and medical evaluation were completed, followed by a run-in period on QD setmelanotide at the dose they were taking in the LTE trial. On Day 1 (Visit 3), patients were randomised 1:1 to receive either QD or QW setmelanotide. Patients on QD 2 mg dose in the LTE trial were randomised to either QD 2 mg or QW 20 mg setmelanotide, patients on QD 2.5 mg to either QD 2.5 mg or QW 25 mg setmelanotide, and patients on QD 3 mg to either QD 3 mg or QW 30 mg setmelanotide. Double-blind conditions were maintained via placebo (dummy) SC injections. From Week 14, all patients crossed over to a 13-week open-label treatment period with QW setmelanotide. Thereafter, in a 3-week follow-up period, all patients returned to their run-in dose of QD setmelanotide. Overall, the median duration of treatment was 29.14 weeks (range: 1.3 to 30.3 weeks) and was similar in both arms. The primary endpoint was the comparison of steady state PK parameters (Cmax, Tmax, Ctrough, and AUC0-tau) for the QD and QW formulations of setmelanotide.

Trial information Top of page
Trial identification
Sponsor protocol code	RM-493-037
Additional study identifiers
ISRCTN number	-
US NCT number	NCT05194124
WHO universal trial number (UTN)	-
Sponsors
Sponsor organisation name	Rhythm Pharmaceuticals, Inc,
Sponsor organisation address	222 Berkeley Street, 12th Floor, Boston, United States, MA 02116
Public contact	Rhythm Clinical Trials, Rhythm Pharmaceuticals, Inc., +1 8572644280, clinicaltrials@rhythmtx.com
Scientific contact	Physician Inquiry Clinical Trials, Rhythm Pharmaceuticals, Inc., +1 8572644280, clinicaltrials@rhythmtx.com
Paediatric regulatory details
Is trial part of an agreed paediatric investigation plan (PIP)	Yes
EMA paediatric investigation plan number(s)	EMEA-002209-PIP01-17
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?	No
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?	Yes
Results analysis stage
Analysis stage	Final
Date of interim/final analysis	19 Oct 2023
Is this the analysis of the primary completion data?	Yes
Primary completion date	19 Oct 2023
Global end of trial reached?	Yes
Global end of trial date	19 Oct 2023
Was the trial ended prematurely?	No
General information about the trial
Main objective of the trial	To compare the pharmacokinetics (PK) of the once daily (QD) and once weekly (QW) formulations of setmelanotide
Protection of trial subjects	The Institutional Review Board (IRB) reviewed all appropriate study documentation in order to safeguard the rights, safety, and well-being of the patients. The study was only conducted at sites where IRB/IEC approval had been obtained. This study was conducted in accordance with: • Consensus ethics principles derived from international ethics guidelines, including the Declaration of Helsinki and Council for International Organizations of Medical Sciences International Ethical Guidelines • The International Council for Harmonisation (ICH) Good Clinical Practices (GCP) Guideline [E6] • Applicable laws and regulatory requirements.
Background therapy	Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, and/or herbal supplements) that the patient was receiving at the time of enrolment or received during the study was recorded along with: • Reason for use. • Dates of administration, including the start and end dates. • Dosage information, including the dose and frequency. GLP 1 receptor agonists could be used up to the dose approved for the treatment of diabetes mellitus (eg, liraglutide up to a daily dose of 1.8 mg) as long as (1) it was not being prescribed for the treatment of obesity, (2) the dose had been stable for at least 3 months prior to enrolment, (3) the patient had not experienced >3% weight loss during the previous 3 months, AND (4) the patient intended to keep the dose stable throughout the course of the study. The Medical Monitor was contacted if there were any questions regarding concomitant or prior therapy. Medications that are approved to treat obesity (eg, orlistat, lorcaserin, phentermine-topiramate, and naltrexone-bupropion) were not allowed within 3 months prior to the first dose of study medication (eg, enrolment) and were prohibited during the study. GLP-1 receptor agonists being prescribed for the treatment of obesity were not allowed. All concomitant medications were to be kept at a stable dose throughout the course of the study unless a dose change was necessary to treat an AE.
Evidence for comparator	Not applicable.
Actual start date of recruitment	20 Dec 2021
Long term follow-up planned	No
Independent data monitoring committee (IDMC) involvement?	No
Population of trial subjects
Number of subjects enrolled per country
Country: Number of subjects enrolled	Netherlands: 3
Country: Number of subjects enrolled	Germany: 2
Country: Number of subjects enrolled	Canada: 2
Country: Number of subjects enrolled	Puerto Rico: 1
Country: Number of subjects enrolled	United Kingdom: 1
Country: Number of subjects enrolled	United States: 10
Worldwide total number of subjects	19
EEA total number of subjects	5
Number of subjects enrolled per age group
In utero	0
Preterm newborn - gestational age < 37 wk	0
Newborns (0-27 days)	0
Infants and toddlers (28 days-23 months)	0
Children (2-11 years)	2
Adolescents (12-17 years)	7
Adults (18-64 years)	10
From 65 to 84 years	0
85 years and over	0

Trial information Top of page

Subject disposition Top of page
Recruitment
Recruitment details	This study recruited 19 patients with rare genetic disorders of obesity (RGDO) in Canada, Europe, Puerto Rico, and the United States from 20 Dec 2019 (first dose 05 Jan 2022). Eligible patients had been treated for at least 6 months with QD setmelanotide in trial RM-493-022. The last patient last visit was 19 Oct 2023.
Pre-assignment
Screening details	Screening assessments included medical history, physical exam, comprehensive skin examination, laboratory tests, blood pressure, hunger scale, body composition, Columbia-Suicide Severity Rating Scale (C-SSRS) form, and energy expenditure evaluation.
Period 1
Period 1 title	Baseline (overall period)
Is this the baseline period?	Yes
Allocation method	Randomised - controlled
Blinding used	Double blind
Roles blinded	Subject, Investigator, Monitor, Data analyst
Blinding implementation details	To maintain the blind during the 13-week randomised treatment period, all patients received placebo injections (mPEG-DSPE vehicle for the QD formulation or FluidCrystal vehicle for the QW formulation) in addition to the setmelanotide injections in a double-dummy fashion. Blinded randomisation occurred via an IRT system.
Arms
Are arms mutually exclusive	Yes
Arm title	QD Setmelanotide (baseline to Week 14)
Arm description	The QD Setmelanotide group includes those patients who were randomised to QD setmelanotide in the randomised double-blind treatment period. Patients were treated from baseline to Week 14.
Arm type	Experimental
Investigational medicinal product name	Setmelanotide QD formulation
Investigational medicinal product code
Other name
Pharmaceutical forms	Solution for injection
Routes of administration	Subcutaneous use
Dosage and administration details	Setmelanotide QD drug product (in mPEG-DSPE vehicle) was provided as a sterile solution at a concentration of 10 mg/mL for administration of dose levels of 2 mg, 2.5 mg, and 3 mg by SC injection.
Investigational medicinal product name	Placebo for QD formulation
Investigational medicinal product code
Other name
Pharmaceutical forms	Solution for injection
Routes of administration	Subcutaneous use
Dosage and administration details	The placebo for the QD formulation consists of the vehicle only (no active ingredient), was visually indistinguishable from the drug product.
Arm title	QW Setmelanotide (baseline to Week 14)
Arm description	The QW Setmelanotide group includes those patients randomised to QW setmelanotide in the randomised double-blind treatment period. Patients were treated from baseline to Week 14.
Arm type	Experimental
Investigational medicinal product name	Setmelanotide QW formulation
Investigational medicinal product code
Other name
Pharmaceutical forms	Solution for injection
Routes of administration	Subcutaneous use
Dosage and administration details	The setmelanotide QW formulation (in FluidCrystal® vehicle) was provided as a sterile solution at a concentration of 30 mg/mL for administration of dose levels of 20 mg, 25 mg, and 30 mg by SC injection. Setmelanotide QW drug product consists of setmelanotide dissolved in a liquid lipid phase containing key excipients, soy phosphatidylcholine, and glycerol dioleate.
Investigational medicinal product name	Placebo for QW formulation
Investigational medicinal product code
Other name
Pharmaceutical forms	Solution for injection
Routes of administration	Subcutaneous use
Dosage and administration details	The placebo for the QW formulation consists of the vehicle only (no active ingredient) and was visually indistinguishable from the QW drug product.
Number of subjects in period 1 QD Setmelanotide (baseline to Week 14) QW Setmelanotide (baseline to Week 14) Started 9 10 Completed 6 9 Not completed 3 1      Adverse event, non-fatal 1 -      Withdrawal by Parent/ Guardian 2 1

Subject disposition Top of page

Baseline characteristics Top of page
Baseline characteristics reporting groups
Reporting group title	QD Setmelanotide (baseline to Week 14)
Reporting group description	The QD Setmelanotide group includes those patients who were randomised to QD setmelanotide in the randomised double-blind treatment period. Patients were treated from baseline to Week 14.
Reporting group title	QW Setmelanotide (baseline to Week 14)
Reporting group description	The QW Setmelanotide group includes those patients randomised to QW setmelanotide in the randomised double-blind treatment period. Patients were treated from baseline to Week 14.
Reporting group values QD Setmelanotide (baseline to Week 14) QW Setmelanotide (baseline to Week 14) Total Number of subjects 9 10 19 Age categorical Units: Subjects Age continuous Units: years     arithmetic mean (standard deviation) 19.6 ( 8.23 ) 21.5 ( 8.42 ) - Gender categorical Units: Subjects     Female 7 4 11     Male 2 6 8 Weight at baseline The most recent weight measurement prior to the first administration of study drug. Units: kilogram(s)     arithmetic mean (standard deviation) 122.20 ( 32.045 ) 98.73 ( 21.898 ) - BMI at baseline The most recent body mass index (BMI) measurement prior to the first administration of study drug. Units: kg/m2     arithmetic mean (standard deviation) 42.491 ( 10.2494 ) 34.598 ( 6.3978 ) - Waist circumference at baseline The most recent waist circumference measurement prior to the first administration of study drug. Units: centimetre     arithmetic mean (standard deviation) 113.79 ( 19.142 ) 105.32 ( 16.437 ) - BMI Z-score at baseline BMI Z-score is a measure of how many standard deviations a child or young person's BMI is above or below the average BMI for their age and gender. Units: Z-score     arithmetic mean (standard deviation) 3.786 ( 1.3269 ) 3.115 ( 1.0146 ) -

Baseline characteristics Top of page

End points Top of page
End points reporting groups
Reporting group title	QD Setmelanotide (baseline to Week 14)
Reporting group description	The QD Setmelanotide group includes those patients who were randomised to QD setmelanotide in the randomised double-blind treatment period. Patients were treated from baseline to Week 14.
Reporting group title	QW Setmelanotide (baseline to Week 14)
Reporting group description	The QW Setmelanotide group includes those patients randomised to QW setmelanotide in the randomised double-blind treatment period. Patients were treated from baseline to Week 14.
Subject analysis set title	QD Regimen - 2.0 mg
Subject analysis set type	Sub-group analysis
Subject analysis set description	QD Regimen - 2.0 mg dose.
Subject analysis set title	QD Regimen - 2.5 mg
Subject analysis set type	Sub-group analysis
Subject analysis set description	QD Regimen - 2.5 mg dose
Subject analysis set title	QD Regimen - 3.0 mg
Subject analysis set type	Sub-group analysis
Subject analysis set description	QD Regimen - 3.0 mg dose
Subject analysis set title	QD-QW-QW Sequence - 20 mg
Subject analysis set type	Sub-group analysis
Subject analysis set description	QD-QW-QW Sequence - 20 mg dose
Subject analysis set title	QD-QW-QW Sequence - 25 mg
Subject analysis set type	Sub-group analysis
Subject analysis set description	QD-QW-QW Sequence - 25 mg dose
Subject analysis set title	QD-QD-QW Sequence - 30 mg
Subject analysis set type	Sub-group analysis
Subject analysis set description	QD-QD-QW Sequence - 30 mg dose
Subject analysis set title	QD-QW-QW Sequence - 30 mg
Subject analysis set type	Sub-group analysis
Subject analysis set description	QD-QW-QW Sequence - 30 mg dose
Subject analysis set title	QD-QD-QW Sequence - 3.0 mg
Subject analysis set type	Sub-group analysis
Subject analysis set description	QD-QD-QW Sequence - 3.0 mg dose

End points Top of page

Primary: Tmax (Visit 2) Top of page
End point title	Tmax (Visit 2) [1]
End point description	Time to reach maximum concentration in hours.
End point type	Primary
End point timeframe	Visit 2
Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The primary endpoints were PK parameters and the objective was to compare PK for the QD and QW formulations of setmelanotide. Each endpoint was reported with descriptive statistics only.
End point values QD Regimen - 2.0 mg QD Regimen - 2.5 mg QD Regimen - 3.0 mg Number of subjects analysed 2 1 16 Units: hour     median (full range (min-max)) 6.91 (5.92 to 7.90) 5.88 (5.88 to 5.88) 6.31 (2.00 to 8.00)
No statistical analyses for this end point

Primary: Tmax (Visit 2) Top of page

Primary: Cmax (Visit 2) Top of page
End point title	Cmax (Visit 2) [2]
End point description	Maximum concentration, determined directly from individual concentration–time data.
End point type	Primary
End point timeframe	Visit 2
Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The primary endpoints were PK parameters and the objective was to compare PK for the QD and QW formulations of setmelanotide. Each endpoint was reported with descriptive statistics only.
End point values QD Regimen - 2.0 mg QD Regimen - 2.5 mg QD Regimen - 3.0 mg Number of subjects analysed 2 1 16 Units: ng/mL     arithmetic mean (standard deviation) 29.4 ( 3.49 ) 44.8 ( 0 ) 59.9 ( 29.6 )
No statistical analyses for this end point

Primary: Cmax (Visit 2) Top of page

Primary: AUC 0-tau (Visit 2) Top of page
End point title	AUC 0-tau (Visit 2) [3]
End point description	The area under the plasma concentration–time curve during the 24-hour (QD) or 168-hour (QW) dosing interval; calculated using the linear trapezoidal rule and allowing for interpolation/extrapolation to 24 hours/168 hours if applicable.
End point type	Primary
End point timeframe	Visit 2
Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The primary endpoints were PK parameters and the objective was to compare PK for the QD and QW formulations of setmelanotide. Each endpoint was reported with descriptive statistics only.
End point values QD Regimen - 2.0 mg QD Regimen - 2.5 mg QD Regimen - 3.0 mg Number of subjects analysed 0 [4] 0 [5] 7 Units: h*ng/mL     arithmetic mean (standard deviation) ( ) ( ) 975 ( 659 )
Notes [4] - No samples were collected for this parameter with this group. [5] - No samples were collected for this parameter with this group.
No statistical analyses for this end point

Primary: AUC 0-tau (Visit 2) Top of page

Primary: AUC last (Visit 2) Top of page
End point title	AUC last (Visit 2) [6]
End point description	Area under the concentration–time curve from time zero to the time of the last quantifiable concentration; calculated using the linear trapezoidal method.
End point type	Primary
End point timeframe	Visit 2
Notes [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The primary endpoints were PK parameters and the objective was to compare PK for the QD and QW formulations of setmelanotide. Each endpoint was reported with descriptive statistics only.
End point values QD Regimen - 2.0 mg QD Regimen - 2.5 mg QD Regimen - 3.0 mg Number of subjects analysed 2 1 16 Units: h*ng/mL     arithmetic mean (standard deviation) 145 ( 24.6 ) 553 ( 0 ) 623 ( 539 )
No statistical analyses for this end point

Primary: AUC last (Visit 2) Top of page

Primary: Tmax (Visit 16) Top of page
End point title	Tmax (Visit 16) [7]
End point description	Time to reach maximum concentration in hours.
End point type	Primary
End point timeframe	Visit 16
Notes [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The primary endpoints were PK parameters and the objective was to compare PK for the QD and QW formulations of setmelanotide. Each endpoint was reported with descriptive statistics only.
End point values QD-QW-QW Sequence - 20 mg QD-QW-QW Sequence - 25 mg QD-QD-QW Sequence - 30 mg QD-QW-QW Sequence - 30 mg Number of subjects analysed 1 1 7 7 Units: hour     median (full range (min-max)) 3.93 (3.93 to 3.93) 5.93 (5.93 to 5.93) 3.05 (0.50 to 6.00) 4.85 (2.03 to 6.03)
No statistical analyses for this end point

Primary: Tmax (Visit 16) Top of page

Primary: Cmax (Visit 16) Top of page
End point title	Cmax (Visit 16) [8]
End point description	Maximum concentration, determined directly from individual concentration–time data.
End point type	Primary
End point timeframe	Visit 16
Notes [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The primary endpoints were PK parameters and the objective was to compare PK for the QD and QW formulations of setmelanotide. Each endpoint was reported with descriptive statistics only.
End point values QD-QW-QW Sequence - 20 mg QD-QW-QW Sequence - 25 mg QD-QD-QW Sequence - 30 mg QD-QW-QW Sequence - 30 mg Number of subjects analysed 1 1 7 7 Units: ng/mL     arithmetic mean (standard deviation) 22.4 ( 0 ) 32.7 ( 0 ) 31.8 ( 28.6 ) 57.3 ( 33.0 )
No statistical analyses for this end point

Primary: Cmax (Visit 16) Top of page

Primary: AUC 0-tau (Visit 16) Top of page
End point title	AUC 0-tau (Visit 16) [9]
End point description	The area under the plasma concentration–time curve during the 24-hour (QD) or 168-hour (QW) dosing interval; calculated using the linear trapezoidal rule and allowing for interpolation/extrapolation to 24 hours/168 hours if applicable.
End point type	Primary
End point timeframe	Visit 16
Notes [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The primary endpoints were PK parameters and the objective was to compare PK for the QD and QW formulations of setmelanotide. Each endpoint was reported with descriptive statistics only.
End point values QD-QW-QW Sequence - 20 mg QD-QW-QW Sequence - 25 mg QD-QD-QW Sequence - 30 mg QD-QW-QW Sequence - 30 mg Number of subjects analysed 1 1 6 6 Units: h*ng/mL     arithmetic mean (standard deviation) 1590 ( 0 ) 2260 ( 0 ) 2470 ( 2890 ) 5010 ( 4000 )
No statistical analyses for this end point

Primary: AUC 0-tau (Visit 16) Top of page

Primary: AUC last (Visit 16) Top of page
End point title	AUC last (Visit 16) [10]
End point description	Area under the concentration–time curve from time zero to the time of the last quantifiable concentration; calculated using the linear trapezoidal method.
End point type	Primary
End point timeframe	Visit 16
Notes [10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The primary endpoints were PK parameters and the objective was to compare PK for the QD and QW formulations of setmelanotide. Each endpoint was reported with descriptive statistics only.
End point values QD-QW-QW Sequence - 20 mg QD-QW-QW Sequence - 25 mg QD-QD-QW Sequence - 30 mg QD-QW-QW Sequence - 30 mg Number of subjects analysed 1 1 7 7 Units: h*ng/mL     arithmetic mean (standard deviation) 446 ( 0 ) 2260 ( 0 ) 1970 ( 2830 ) 3540 ( 3910 )
No statistical analyses for this end point

Primary: AUC last (Visit 16) Top of page

Primary: Ctrough (Visit 3) Top of page
End point title	Ctrough (Visit 3) [11]
End point description	Concentration at the end of the dosing interval, prior to subsequent dose administration.
End point type	Primary
End point timeframe	Visit 3
Notes [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The primary endpoints were PK parameters and the objective was to compare PK for the QD and QW formulations of setmelanotide. Each endpoint was reported with descriptive statistics only.
End point values QD-QW-QW Sequence - 20 mg QD-QW-QW Sequence - 25 mg QD-QW-QW Sequence - 30 mg QD-QD-QW Sequence - 3.0 mg Number of subjects analysed 2 1 7 9 Units: ng/mL     arithmetic mean (standard deviation) 5.17 ( 0.856 ) 4.36 ( 0 ) 16.6 ( 16.3 ) 11.7 ( 13.5 )
No statistical analyses for this end point

Primary: Ctrough (Visit 3) Top of page

Primary: Ctrough (Visit 7) Top of page
End point title	Ctrough (Visit 7) [12]
End point description	Concentration at the end of the dosing interval, prior to subsequent dose administration.
End point type	Primary
End point timeframe	Visit 7
Notes [12] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The primary endpoints were PK parameters and the objective was to compare PK for the QD and QW formulations of setmelanotide. Each endpoint was reported with descriptive statistics only.
End point values QD-QW-QW Sequence - 20 mg QD-QW-QW Sequence - 25 mg QD-QW-QW Sequence - 30 mg QD-QD-QW Sequence - 3.0 mg Number of subjects analysed 0 [13] 1 7 7 Units: ng/mL     arithmetic mean (standard deviation) ( ) 9.54 ( 0 ) 15.6 ( 13.3 ) 12.2 ( 7.62 )
Notes [13] - No samples were collected for this endpoint in this group
No statistical analyses for this end point

Primary: Ctrough (Visit 7) Top of page

Primary: Ctrough (Visit 11) Top of page
End point title	Ctrough (Visit 11) [14]
End point description	Concentration at the end of the dosing interval, prior to subsequent dose administration.
End point type	Primary
End point timeframe	Visit 11
Notes [14] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The primary endpoints were PK parameters and the objective was to compare PK for the QD and QW formulations of setmelanotide. Each endpoint was reported with descriptive statistics only.
End point values QD-QW-QW Sequence - 20 mg QD-QW-QW Sequence - 25 mg QD-QW-QW Sequence - 30 mg QD-QD-QW Sequence - 3.0 mg Number of subjects analysed 1 1 6 7 Units: ng/mL     arithmetic mean (standard deviation) 11.1 ( 0 ) 6.43 ( 0 ) 20.1 ( 13.7 ) 12.3 ( 11.4 )
No statistical analyses for this end point

Primary: Ctrough (Visit 11) Top of page

Adverse events Top of page
Adverse events information
Timeframe for reporting adverse events	From baseline to Week 26.
Adverse event reporting additional description	The patients were randomised to and treated with QD or QW setmelanotide in a 13-week randomised double-blind treatment period. Thereafter, patients entered a 13-week, non-randomised, open-label treatment period during which all patients were treated with QW setmelanotide.
Assessment type	Systematic
Dictionary used for adverse event reporting
Dictionary name	MedDRA
Dictionary version	26.1
Reporting groups
Reporting group title	QD Setmelanotide
Reporting group description	-
Reporting group title	QW Setmelanotide
Reporting group description	-
Serious adverse events QD Setmelanotide QW Setmelanotide Total subjects affected by serious adverse events      subjects affected / exposed 0 / 9 (0.00%) 0 / 10 (0.00%)      number of deaths (all causes) 0 0      number of deaths resulting from adverse events 0 0
Frequency threshold for reporting non-serious adverse events: 5%
Non-serious adverse events QD Setmelanotide QW Setmelanotide Total subjects affected by non serious adverse events      subjects affected / exposed 9 / 9 (100.00%) 9 / 10 (90.00%) Neoplasms benign, malignant and unspecified (incl cysts and polyps) Melanocytic naevus      subjects affected / exposed 1 / 9 (11.11%) 1 / 10 (10.00%)      occurrences all number 1 1 Vascular disorders Haematoma      subjects affected / exposed 1 / 9 (11.11%) 1 / 10 (10.00%)      occurrences all number 1 2 General disorders and administration site conditions Injection site pain      subjects affected / exposed 4 / 9 (44.44%) 6 / 10 (60.00%)      occurrences all number 11 11 Injection site erythema      subjects affected / exposed 4 / 9 (44.44%) 4 / 10 (40.00%)      occurrences all number 6 9 Fatigue      subjects affected / exposed 2 / 9 (22.22%) 0 / 10 (0.00%)      occurrences all number 2 0 Injection site induration      subjects affected / exposed 2 / 9 (22.22%) 5 / 10 (50.00%)      occurrences all number 2 10 Injection site bruising      subjects affected / exposed 1 / 9 (11.11%) 1 / 10 (10.00%)      occurrences all number 1 2 Injection site haemorrhage      subjects affected / exposed 1 / 9 (11.11%) 3 / 10 (30.00%)      occurrences all number 1 6 Injection site pruritus      subjects affected / exposed 1 / 9 (11.11%) 4 / 10 (40.00%)      occurrences all number 1 5 Hangover      subjects affected / exposed 0 / 9 (0.00%) 1 / 10 (10.00%)      occurrences all number 0 2 Injection site inflammation      subjects affected / exposed 0 / 9 (0.00%) 1 / 10 (10.00%)      occurrences all number 0 1 Injection site mass      subjects affected / exposed 0 / 9 (0.00%) 1 / 10 (10.00%)      occurrences all number 0 1 Immune system disorders Food allergy      subjects affected / exposed 1 / 9 (11.11%) 0 / 10 (0.00%)      occurrences all number 1 0 Seasonal allergy      subjects affected / exposed 1 / 9 (11.11%) 0 / 10 (0.00%)      occurrences all number 1 0 Reproductive system and breast disorders Menstruation irregular      subjects affected / exposed 1 / 9 (11.11%) 1 / 10 (10.00%)      occurrences all number 1 1 Dysmenorrhoea      subjects affected / exposed 0 / 9 (0.00%) 1 / 10 (10.00%)      occurrences all number 0 1 Respiratory, thoracic and mediastinal disorders Oropharyngeal pain      subjects affected / exposed 1 / 9 (11.11%) 2 / 10 (20.00%)      occurrences all number 1 2 Cough      subjects affected / exposed 0 / 9 (0.00%) 2 / 10 (20.00%)      occurrences all number 0 2 Dry throat      subjects affected / exposed 0 / 9 (0.00%) 1 / 10 (10.00%)      occurrences all number 0 1 Psychiatric disorders Libido decreased      subjects affected / exposed 1 / 9 (11.11%) 0 / 10 (0.00%)      occurrences all number 1 0 Depressed mood      subjects affected / exposed 0 / 9 (0.00%) 1 / 10 (10.00%)      occurrences all number 0 1 Mood altered      subjects affected / exposed 0 / 9 (0.00%) 1 / 10 (10.00%)      occurrences all number 0 1 Investigations Hepatic enzyme increased      subjects affected / exposed 0 / 9 (0.00%) 1 / 10 (10.00%)      occurrences all number 0 1 Injury, poisoning and procedural complications Ligament sprain      subjects affected / exposed 1 / 9 (11.11%) 0 / 10 (0.00%)      occurrences all number 1 0 Heat stroke      subjects affected / exposed 0 / 9 (0.00%) 1 / 10 (10.00%)      occurrences all number 0 1 Meniscus injury      subjects affected / exposed 0 / 9 (0.00%) 1 / 10 (10.00%)      occurrences all number 0 1 Cardiac disorders Palpitations      subjects affected / exposed 1 / 9 (11.11%) 1 / 10 (10.00%)      occurrences all number 1 1 Nervous system disorders Seizure      subjects affected / exposed 1 / 9 (11.11%) 0 / 10 (0.00%)      occurrences all number 4 0 Headache      subjects affected / exposed 2 / 9 (22.22%) 1 / 10 (10.00%)      occurrences all number 3 7 Dizziness      subjects affected / exposed 0 / 9 (0.00%) 1 / 10 (10.00%)      occurrences all number 0 1 Sleep paralysis      subjects affected / exposed 0 / 9 (0.00%) 1 / 10 (10.00%)      occurrences all number 0 1 Gastrointestinal disorders Nausea      subjects affected / exposed 3 / 9 (33.33%) 1 / 10 (10.00%)      occurrences all number 8 3 Diarrhoea      subjects affected / exposed 3 / 9 (33.33%) 1 / 10 (10.00%)      occurrences all number 4 1 Vomiting      subjects affected / exposed 2 / 9 (22.22%) 0 / 10 (0.00%)      occurrences all number 4 0 Abdominal pain upper      subjects affected / exposed 1 / 9 (11.11%) 0 / 10 (0.00%)      occurrences all number 2 0 Skin and subcutaneous tissue disorders Skin hyperpigmentation      subjects affected / exposed 3 / 9 (33.33%) 1 / 10 (10.00%)      occurrences all number 3 3 Acne      subjects affected / exposed 1 / 9 (11.11%) 0 / 10 (0.00%)      occurrences all number 1 0 Rash      subjects affected / exposed 1 / 9 (11.11%) 0 / 10 (0.00%)      occurrences all number 1 0 Alopecia      subjects affected / exposed 0 / 9 (0.00%) 1 / 10 (10.00%)      occurrences all number 0 1 Eczema      subjects affected / exposed 0 / 9 (0.00%) 1 / 10 (10.00%)      occurrences all number 0 1 Papule      subjects affected / exposed 0 / 9 (0.00%) 1 / 10 (10.00%)      occurrences all number 0 1 Musculoskeletal and connective tissue disorders Arthralgia      subjects affected / exposed 1 / 9 (11.11%) 0 / 10 (0.00%)      occurrences all number 1 0 Infections and infestations Nasopharyngitis      subjects affected / exposed 2 / 9 (22.22%) 3 / 10 (30.00%)      occurrences all number 3 6 Gastroenteritis      subjects affected / exposed 1 / 9 (11.11%) 0 / 10 (0.00%)      occurrences all number 1 0 Gastroenteritis viral      subjects affected / exposed 1 / 9 (11.11%) 0 / 10 (0.00%)      occurrences all number 1 0 Tinea versicolour      subjects affected / exposed 1 / 9 (11.11%) 0 / 10 (0.00%)      occurrences all number 1 0 COVID-19      subjects affected / exposed 0 / 9 (0.00%) 1 / 10 (10.00%)      occurrences all number 0 1 Otitis media      subjects affected / exposed 0 / 9 (0.00%) 1 / 10 (10.00%)      occurrences all number 0 1 Subcutaneous abscess      subjects affected / exposed 0 / 9 (0.00%) 1 / 10 (10.00%)      occurrences all number 0 1 Metabolism and nutrition disorders Decreased appetite      subjects affected / exposed 1 / 9 (11.11%) 0 / 10 (0.00%)      occurrences all number 1 0 Appetite disorder      subjects affected / exposed 0 / 9 (0.00%) 1 / 10 (10.00%)      occurrences all number 0 1

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Substantial protocol amendments (globally)
Were there any global substantial amendments to the protocol? Yes
Date	Amendment
10 Dec 2021	Protocol Version 2.0 changes: • Corrected duration of follow-up period from 4-week follow-up period to 3- week follow-up period based on change in Schedule of Assessments • Changed QD PK sampling to the first day of the run-in period instead of at the end of the Run-in period • 2.5 mg QD/25 mg QW dose levels were included in methodology, synopsis, diagnosis and main criteria for inclusion, investigational product, dosage, and mode of administration • Corrected duration of study based on change in the follow-up period to 30 weeks • Added clarity/specificity to endpoints • Corrected an error, i.e., 50% effective concentration=0.27 nM • Specified formula to calculate eGFR • Added PHQ-9 score of ≥15 during screening for depression • Added ability for patients to get re-screened once if the screen failure is due to an entry criterion result that may change over time • Added text on drug accountability, reconciliation, and record maintenance • Added a section and explained unblinding • Added details for measuring height and weight • Added clarification around administration of patient-reported and caregiver-reported Hunger and Hyperphagia questionnaires • Added optional activity sensor sub-study • To ensure better safety of patients, the outpatient measurements of vital signs were to be re-checked either by the patient’s primary care physician or at the investigative site • Added specificity to distinguish injection sites for QW formulation from those with the QD formulation • Added general text about monitoring for depression and suicidality • Added clarification on baseline/screening version of the C-SSRS scale • Added PHQ-9 to monitor for depression • Added specificity to analysis in terms of change and percentage change from baseline to Week 14 • Added clarification of region measurement, length, and width as appropriate during in-clinical visits and if possible during telehealth visits
21 Mar 2022	Protocol Version 3.0 changes: • Revised study objectives and endpoints to capture PK profile and adjusted PK sample collection timepoints to better capture both QD and QW PK profiles • Moved efficacy endpoint to exploratory endpoints and expanded exploratory endpoints to yield additional supportive information • Statistical analyses were updated to reflect revised objectives and endpoints • Included an option for possible blinded interim analyses • Modified procedures for telehealth visits • Clarified language around re-screening criteria • Included additional guidance on conduct for the optional sub-study
07 Jul 2022	Protocol Version 4.0 changes: • Included language to require re-consent of patients who reach the age of consent during the study (as applicable) • Removed optional activity sensor sub-study • Provided flexibility for the Investigator to prioritize sampling for patients <18 years of age to minimize excessive venipunctures; included this flexibility for all assessments for patients <18 years of age • Widened predose PK sampling window to within 30 minutes of dosing; widened certain post dose PK sampling windows to ±30 minutes • Provided clarity around PK sampling timepoints to ensure characterization of PK profile for QD and QW • Included new indication for setmelanotide (currently in US) • Included criteria for determining study termination and re-organized content flow in Section 5.0 • Broadened exclusion criterion #9 to include hypersensitivity to active investigational product • Revised exclusion criteria #12 and #13 to include patients who are either legally protected or patients who are related to anyone responsible for the conduct of the study • Aligned language to reflect intent of voluntary study participation • Amended language to describe criteria for study and/or site closure (Germany)
Interruptions (globally)
Were there any global interruptions to the trial? No
Limitations and caveats
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
None reported

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